Novel aerosol formulations of granisetron and uses thereof

ABSTRACT

Aerosol formulations of granisetron useful for pulmonary delivery are provided. The formulations are useful in the reduction, elimination or prevention of nausea and vomiting associated with chemotherapy, radiation therapy, and surgery. Also provided are novel methods to treat chemotherapy-induced nausea and vomiting (CINV), radiation-induced nausea and vomiting (RINV), and post-operative nausea and vomiting (PONV) using the inhalation formulations.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Nonprovisional applicationSer. No. 15/156,796, filed on May 17, 2016, which is a continuation ofU.S. Nonprovisional application Ser. No. 14/323,089, filed on Jul. 3,2014, now, abandoned, which claims benefit to U.S. ProvisionalApplication Ser. No. 61/842,825, filed on Jul. 3, 2013, and U.S.Provisional Application Ser. No. 61/909,982, filed on Nov. 27, 2013,which are herein incorporated by reference in their entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable.

THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT

Not Applicable.

INCORPORATION-BY-REFERENCE OF THE MATERIAL ON THE COMPACT DISC

Not Applicable.

BACKGROUND OF THE INVENTION Field of the Invention

Provided herein are novel aerosol inhalation formulations of granisetronfor pulmonary delivery; and uses thereof in the reduction, eliminationor prevention of nausea and vomiting associated with chemotherapy,radiation therapy and surgery. Also provided are methods to treatchemotherapy-induced nausea and vomiting (CINV), radiation-inducednausea and vomiting (RINV), and post-operative nausea and vomiting(PONV) using the inhalation formulations.

Description of the Related Art Including Information Disclosed Under 37CFR 1.97 and 1.98

Cancer is one of the major causes of death in the modern world. Majortherapies to treat cancers include chemotherapy, radiation therapy andsurgery. Nausea and vomiting are among the most common side-effects ofthese treatments. Patients receiving highly emetogenic agents maypostpone, or even refuse, potentially curative treatments. Increasing ofblood level of serotonin and activation of the 5-HT₃ receptors in thechemoreceptor trigger zone in the brain are believed to be related tothe emetic responses to cancer treatments [Hornby, 2001].

Granisetron is a 5-HT₃ receptor antagonist used mainly as an antiemeticoften following chemotherapy, radiation therapy and surgery. Granisetronis believed to block 5-HT₃ receptors in the chemoreceptor trigger zone.It is believed to reduce the activity of the vagus nerve, hence thecompound deactivates the vomiting center in the medulla oblongata[Aapro, 2004]. FIG. 1 shows the skeletal formula of granisetron.

Currently, granisetron is administered either through injection (slow IVor IM) or as oral tablets. Injection of granisetron, although effectivein reducing or preventing nausea and vomiting, is inconvenient, invasiveand causes pain to the patients. Existing forms of oral granisetrontablets can be difficult to swallow and may be undesirable to somepatients requiring anti-emetic therapy, especially those patients whohave severe nausea or vomiting.

Thus, there remains a need for new formulations and for novel methods toadminister granisetron. The formulations, and methods described hereinare directed toward this end.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present invention provides novel aerosol formulationscomprising granisetron useful for pulmonary delivery to a subject. Inone embodiment, the aerosol formulations are administered by inhalation.In another embodiment, the aerosol formulations are delivered into thecirculation via the pulmonary tract. In one embodiment, the subject is apatient such as a cancer patient.

In certain aspects, the present invention provides pharmaceuticalaerosol inhalation formulations comprising granisetron.

In certain aspects, the aerosol formulations of the present inventionare useful for the reduction, elimination or prevention of variousmedical conditions including chemotherapy-induced nausea and vomiting(CINV), radiation-induced nausea and vomiting (RINV), and post-operativenausea and vomiting (PONV).

In another aspect, the present invention provides methods of treating acondition of nausea or vomiting, wherein the method comprises pulmonaryadministration of a pharmaceutically acceptable amount of the aerosolformulations of the present invention, and wherein the aerosolformulations are administered into the pulmonary tract by inhalation.

In yet another aspect, the present invention provides methods forpulmonary delivery of granisetron to a subject that comprise having thesubject inhale a pharmaceutically acceptable amount of the aerosolformulation of the present invention through the subject's mouth intothe circulation via the pulmonary tract. In one embodiment, the subjectis a cancer patient.

In yet another aspect, the present invention provides a method forpulmonary delivery of granisetron to a subject, where the methodcomprises having the subject inhale a pharmaceutically acceptable amountof the aerosol formulation of the present invention through thesubject's nose into the circulation via the pulmonary tract. In oneembodiment, the subject is a cancer patient.

In yet another aspect, with respect to the aerosol formulations ormethods of the present invention, the pulmonary administration of theaerosol formulations minimizes the first pass metabolism before the drugreaches the target receptors since there is rapid transport from thealveolar epithelium into the circulation. In addition, the pulmonaryadministration of the aerosol formulations of the present invention byinhalation avoids gastrointestinal intolerance which is typical fornausea and vomiting sufferers.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing detailed description.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1: Skeletal Formula of Granisetron

FIG. 2: A typical particle size distribution of spray dried granisetronpowder.

FIG. 3: A typical particle size distribution of jet milled granisetronpowder.

FIG. 4: The aerosol particle size distribution (ASPD) of 3 runs of theLH201 blend at 60 LPM and under ambient temperature and humidityconditions of ˜22° C. and 20% RH.

FIG. 5: The ASPD of 3 runs of the ML001 blend at 60 LPM and underambient temperature and humidity conditions of ˜22° C. and 20% RH.

FIG. 6: The ASPD of 3 runs of the ML001/LH300 blend at 60 LPM and underambient temperature and humidity conditions of ˜22° C. and 20% RH.

FIG. 7: The ASPD of 3 runs of the SV003/LH300 blend at 60 LPM and underambient temperature and humidity conditions of ˜22° C. and 20% RH.

FIG. 8: The ASPD of 3 runs of the ML001/LH300 blend at 60 LPM and at acontrolled temperature and humidity of 23° C. and 50% RH, respectively.

FIG. 9: The ASPD of 3 runs of the SV003/LH300 blend at 60 LPM and at acontrolled temperature and humidity of 23° C. and 50% RH, respectively.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel aerosol formulations comprisinggranisetron useful for pulmonary delivery to a subject. In oneembodiment, the aerosol formulations are administered by inhalation. Inanother embodiment, the aerosol formulations are delivered into thecirculation via the pulmonary tract. The subject for whom the aerosolformulations are administered may be a mammal, such as a human. In oneembodiment, the subject is a patient; in particular, the subject is acancer patient.

The present invention also provides pharmaceutical aerosol inhalationformulations comprising powdered granisetron. In one embodiment, withrespect to the aerosol inhalation formulation, the mass medianaerodynamic diameter (MMAD) of powdered granisetron is between 0.05 and20 microns, preferably the powdered granisetron has an MMAD between 0.5and 5 microns. In another embodiment, the aerosol formulations areuseful for pulmonary delivery of granisetron to a subject. In oneembodiment, the subject is a cancer patient.

In addition, the present invention provides inhalable pharmaceuticalaerosol formulations comprising powdered granisetron, wherein the MMADof powdered granisetron is between 0.05 and 20 microns; and wherein theformulations are useful for pulmonary delivery to a subject, where thesubject is a cancer patient. In one embodiment, the aerosol formulationsare delivered into the circulation via pulmonary tract of the subjectand the subject is a cancer patient.

In certain aspects, the aerosol formulations of the present inventionare useful for the reduction, elimination, or prevention of nausea andvomiting associated with various medical conditions includingchemotherapy-induced nausea and vomiting (CINV), radiation-inducednausea and vomiting (RINV), and post-operative nausea and vomiting(PONV).

In certain aspects, the aerosol formulations of the present inventionare administered by subjects via an inhaler allowing granisetron toenter the circulation rapidly.

In certain aspects, the aerosol formulations of the present inventionprovide a novel route of administration of granisetron to subjects whohave severe nausea or vomiting and not willing to or not able to swallowor to be injected.

In certain aspect, the aerosol formulations of the present inventioncontains granisetron that is in a solute form. In certain aspect, theaerosol formulations of the present invention contains granisetron thatis in a powdered form.

In certain aspect, the aerosol formulations of the present inventioncontains granisetron that is in a powdered form, and the powderedgranisetron is in a dry powder form.

In certain aspect, the aerosol formulations of the present inventioncontains granisetron that is in a powdered form, and the powderedgranisetron is in a suspension. In certain aspect, the powderedgranisetron suspension is in a liquid selected from a group consistingof propellants, hybrid propellants, propellants with stabilizers,propellants with surfactants, propellants with diluents, propellantswith cosolvents, water, buffer, and combinations thereof.

In certain aspect, the aerosol formulations of the present inventioncontains granisetron that is a solute in a solution, and the solvent isselected from a group consisting of propellants, hybrid propellants,cosolvents, cosolvent mixture, organic solvents, water, buffers, andcombinations thereof.

When the granisetron in the aerosol formulations is in a powdered form,the powdered granisetron is produced by one or more particle engineeringprocesses [Chow et al., 2007]. For example, the powdered granisetron maybe produced by a mechanical micronization operation selected from thegroup consisting of crushing, cutting, bashing, milling, and grinding.In another embodiment, the powdered granisetron is produced by aprecipitation process, such as spray drying, solution precipitation,lyophilization, or combinations of the foregoing. Yet in anotherembodiment, the powered granisetron is produced by one of moreprecipitation processes followed by one or more mechanical micronizationprocesses.

In one embodiment, the powdered granisetron of the aerosol formulationsis produced by a spray drying process. The spray drying process may befollowed by a cyclone separation/filtering process.

In another embodiment, the powdered granisetron of the aerosolformulations is produced by a direct controlled crystallization process.The direct controlled crystallization process may utilize an antisolventprecipitation technique. Moreover, the size range of the crystallinesmay be controlled by one or more growth-retarding stabilizing additives.

In yet another embodiment, the powdered granisetron of the aerosolformulations is produced by a supercritical fluid process. Thesupercritical fluid process is selected from the group consisting ofrapid expansion of supercritical solution (RESS), solution enhanceddiffusion (SEDS), gas-anti solvent (GAS), supercritical antisolvent(SAS), precipitation from gas-saturated solution (PGAS), precipitationwith compressed antisolvent (PCA) and aerosol solvent extraction system(ASES).

In a particular embodiment, with respect to the aerosol formulations,the powdered granisetron is produced by supercritical fluid process, andthe process is rapid expansion of supercritical solution (RESS) process.In another particular embodiment, the process is solution enhanceddiffusion (SEDS) process. In yet another particular embodiment, theprocess is gas-anti-solvent (GAS) process. In yet another particularembodiment, the process is supercritical-anti-solvent (SAS) process. Inyet another particular embodiment, the process is precipitation fromgas-anti-solvent (PGAS) process. In yet another particular embodiment,the process is precipitation with compressed anti-solvent (PCA) process.In yet another particular embodiment, the process is aerosol solventextraction system (ASES) process. In yet another particular embodiment,the process is any combinations of the foregoing.

In a more particular embodiment, with respect to the aerosolformulations, the powdered granisetron is produced by a supercriticalfluid process, and the supercritical fluid process is rapid expansion ofsupercritical solution process.

In one embodiment, with respect to the aerosol formulations, the meangeometric diameter of powdered granisetron is at least 0.01 microns, atleast 0.05 microns, at least 0.1 microns, at least 0.25 microns, atleast 0.5 microns, at least 0.75 microns, at least 0.9 microns, at least1 microns, at least 1.25 microns, at least 1.5 microns, at least 1.75microns, or even at least 2.0 microns. The mean geometric diameter ofpowdered granisetron is at most 20 microns, at most 15 microns, at most12 microns, at most 10 microns, at most 9 microns, at most 8 microns, atmost 7.5 microns, at most 7 microns, at most 6.5 microns, at most 6.0microns, at most 5.75 microns, at most 5.5 microns, at most 5.25microns, at most 5.0 microns, at most 4.75 microns, at most 4.5 microns,at most 4.25 microns, at most 4.0 microns, at most 3.75 microns, at most3.5 microns, at most 3.25 microns, and even at most 3.0 microns. Themean geometric diameter of powdered granisetron generally ranges frombetween 0.05 and 30 microns, preferably between 0.1 and 20 microns,between 0.2 and 15 microns, between 0.3 and 10 microns, and morepreferably between 0.5 and 5 microns. Advantageously, the mean geometricdiameter of powdered granisetron is between 1 and 3 microns.

In a particular embodiment, with respect to the aerosol formulations,the mean geometric diameter of powdered granisetron is between 0.05 and20 microns, preferably between 0.5 and 4 microns, more preferablybetween 1 and 3 microns.

In one embodiment, with respect to the aerosol formulations, thepowdered granisetron has an MMAD of at least 0.01 microns, at least 0.05microns, at least 0.1 microns, at least 0.25 microns, at least 0.5microns, at least 0.75 microns, at least 0.9 microns, at least 1microns, at least 1.25 microns, at least 1.5 microns, at least 1.75microns, or even at least 2.0 microns. The MMAD of powdered granisetronis at most 30 microns, at most 20 microns, at most 15 microns, at most10 microns, at most 9 microns, at most 8 microns, at most 7.5 microns,at most 7 microns, at most 6.5 microns, at most 6.0 microns, at most5.75 microns, at most 5.5 microns, at most 5.25 microns, at most 5.0microns, at most 4.75 microns, at most 4.5 microns, at most 4.25microns, at most 4.0 microns, at most 3.75 microns, at most 3.5 microns,at most 3.25 microns, and even at most 3.0 microns. Generally, the MMADof the powdered granisetron is between 0.05 and 30 microns, preferablybetween 0.1 and 20 microns, between 0.2 and 15 microns, more preferablybetween 0.3 and 10 microns, between 0.5 and 5 microns, and especiallybetween 1 and 3 microns.

In a particular embodiment, with respect to the aerosol formulations,the powdered granisetron has an MMAD between 0.05 and 20 microns,preferably between 0.5 and 4 microns, and more preferably between 1 and3 microns.

In one embodiment, with respect to the aerosol formulations, the meangeometric diameter and the MMAD of powdered granisetron are similar.Alternatively, in another embodiment, the mean geometric diameter andthe MMAD of powdered granisetron are different. In one embodiment, wherethe mean geometric diameter and the MMAD of powdered granisetron aredifferent, the difference is due to the morphology of the granisetronparticles.

The powdered granisetron may be a solvate, hydrate, organic salt,inorganic salt, ester, or free base. The powdered granisetron may alsobe amorphous, crystalline, or polymorphous. Preferably, the granisetronis a chloride, bromide, iodide, mesylate, methanesulphonate,para-toluenesulphonate, or methyl sulphate salt. More preferably, thegranisetron is in the form of a hydrochloride, anhydrous, monohydrate ordihydrate.

In one embodiment, the granisetron particles of the aerosol formulationsare amorphous.

In one embodiment, the granisetron particles of the aerosol formulationsare crystallines. In another embodiment, the shape of the granisetronparticles is one of the group consisting of spherical, ellipsoidal,cubical, diamond, rectangular, orthorhombic, triangular, hexagonal,needlelike, and porous. Preferably, the granisetron particles of theaerosol formulations are spherical.

In one embodiment, the granisetron particles of the aerosol formulationsare polymorphous. In another embodiment, the shapes of the granisetronparticles are two of more from the group consisting of spherical,ellipsoidal, cubical, diamond, rectangular, orthorhombic, triangular,hexagonal, needlelike, and porous.

In one embodiment, with respect to the aerosol formulations, theproportion of granisetron particles with aerodynamic diameters less than5 μm is at least 5%, at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 70%, and preferably at least70%. In another embodiment, the proportion of granisetron particles withaerodynamic diameters less than 5 μm is at most 100%, at most 99%, atmost 95%, at most 90%, at most 85%, at most 80%, at most 75%, at most70%, at most 65%, at most 60%, at most 55%, at most 50%, at most 45%, atmost 40%, at most 35%, at most 30%, at most 25%, at most 20%, at most17.5%, at most 15%, and even at most 12.5%.

In one embodiment, with respect to the aerosol formulations, theproportion of granisetron particles with aerodynamic diameters less than5 μm is 10% to 100%, preferably from 70% to 100%. In another embodiment,the proportion of granisetron particles with aerodynamic diameters lessthan 5 μm is from 20 to 80%, preferably from 30% to 70%. In a furtherembodiment, the proportion of granisetron particles with aerodynamicdiameters less than 5 μm is 10% to 30%.

In one embodiment, with respect to the aerosol formulations, the fineparticle fraction (FPF) of granisetron is 10% to 100%. In certainembodiments, the minimum FPF is 50%, for instance, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, and even at least 90%. In one embodiment, the FPF ofgranisetron is from 70% to 100%. The FPF of granisetron may also rangefrom 30% to 70%. In another embodiment, the maximum FPF of granisetronis 50% or less, for instance, the maximum FPF of granisetron is at most40%, at most 35%, at most 30%, at most 25%, at most 20%, at most 17.5%,at most 15%, at most 12.5%, and even at most 10%. In one embodiment, theFPF of the granisetron is 10% to 30%.

In the aerosol formulations according to the invention, the granisetronhas respirable fraction of 10% or more, preferably 15% or more, 20% ormore, 25% or more, 35% or more, 40% or more, 45% or more, 50% or more,more preferably 75% or more, and even 90% or more.

In one embodiment, the aerosol formulations do not comprise anexcipient.

In another embodiment, the aerosol formulations further comprise apharmaceutically acceptable excipient. The excipient is any excipientacceptable for pulmonary delivery. More particularly, the excipient isany inhalable excipient.

In aerosol formulations containing an excipient, the excipient isselected from the group consisting of carbohydrates, amino acids,polypeptides, lipids, buffers, salts, polyalcohols, and mixturesthereof. In yet another embodiment, the excipient is selected from thegroup consisting of galactose, mannose, sorbose, lactose, glucose,trehalose, raffinose, maltodextrins, dextrans, mannitol, xylitol, andmixtures thereof. In yet another embodiment, the excipient is selectedfrom the group consisting of alanine, glycine, tryptophan, tyrosine,leucine, phenylalanine, and mixtures thereof. In yet another embodiment,the excipient is selected from the group consisting of oleates,stearates, myristates, alkylethers, alkyl arylethers, sorbates,polyvinylpyrrolidone (PVP) and mixtures thereof. In yet anotherembodiment, the excipient is selected from the group consisting of1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3-heptafluoro-n propane(P227), 2H, 3H-perfluoropentane (HPFP) and mixtures thereof. In yetanother embodiment, the excipient is any combinations of the foregoing.

In certain embodiments, the aerosol formulations are pressurized metereddose formulations. In certain embodiments, the aerosol formulations aredry powder formulations. In certain embodiments, the aerosolformulations are nebulizer formulations.

Dry Power Formulations

In a particular embodiment, the formulation is a dry powder formulationcontaining an excipient, where the excipient is lactose, glucose, or amixture of lactose and glucose.

In the dry powder formulations containing a pharmaceutically acceptableexcipient, the excipient consists of powders with an average particlessize of <5 to 200 microns, from 1 to 150 microns, or from 5 to 100microns. The excipient may consists of powders of the same substancewith an average particle size of <5 to 200 microns, from 1 to 150microns, or from 5 to 100 microns. There may also be a mixture ofpowders in which the average particle size is from <5 to 200 microns,from 1 to 150 microns, or from 5 to 100 microns.

In particular, where the dry powder formulations further comprise apharmaceutically acceptable excipient and the excipient consists ofpowders with an average particle size of <5 to 200 microns, theexcipient may be a mixture of the same substance with different particlesize distributions. For example, in one embodiment the pharmaceuticallyacceptable excipient having an average particle size of <5 to 200microns with different particle size distributions is a mixture ofcoarser powders and finer powders of the same substance, where the finerpowders have an average particle size from <5 to 50 microns and thecoarser powders have an average particle size of 50 to 200 microns. Thefiner powders may have an average particle size from <5 to 45 microns,from 10 to 40 microns, from 15 to 35 microns, or from 20 to 30 microns,while the coarser powders may have an average particle size from 60 to90 microns, from 65 to 85 microns, or from 70 to 80 microns.Alternatively, the finer powders may have an average particle size from1 to 10 microns, from 1 to 7.5 microns, from 1 to 5 microns, or from 2to 5 microns, while the coarser powders may have an average particlesize from 20 to 60 microns, from 20 to 25 microns, from 30 to 60microns, from 40 to 60 microns, or from 50 to 60 microns. In someembodiments, the coarser powders have an average particle size from 50to 90 microns, from 65 to 85 microns, or from 70 to 80 microns. Theproportion of finer excipient powders may be 0.1% to 99% of the totalamount of excipient powders.

In another embodiment, with respect to the dry powder formulations, thepharmaceutically acceptable excipient having an average particle size of<5 to 200 microns with different particle size distributions is amixture of finer powders, coarser powders, and much coarser powders ofthe same substance, where the finer powders have an average particlesize of <5 to 20 microns, the coarser powders have an average particlessize of 20 to 60 microns, and the much coarser powders have an averageparticles size of 60 to 200 microns. Preferably, the finer powders havean average particle size of <5 to 10 microns, the coarser powders havean average particles size of 25 to 45 microns, and the much coarserpowders have an average particles size of 75 to 90 microns. Theproportion of finer excipient powders may be 0.1% to 99% of the totalamount of excipient powders.

In addition, in the dry powder formulations, the pharmaceuticallyacceptable excipient may be a mixture of different substances withsimilar particle size distributions in which the average particle sizeis from <5 to 200 microns or from 5 to 100 microns.

Advantageously, the pharmaceutically acceptable excipient in the drypowder formulations is a mixture of different substances with differentparticle size distributions in which the average particle sizes are from<5 to 200 microns. Namely, the pharmaceutically acceptable excipient ofthe dry powder formulations is a mixture of finer powders having anaverage particle size of <5 to 50 microns and coarser powders with anaverage particles size of 50 to 200 microns; the finer powders and thecoarser powders being different substances. The proportion of finerexcipient powders may be 0.1% to 99% of the total amount of excipientpowders.

In another embodiment, the pharmaceutically acceptable excipient of thedry powder formulations is a mixture of finer powders having an averageparticle size of <5 to 20 microns, coarser powders having an averageparticles size of 20 to 60 microns, and much coarser powders having anaverage particles size of 60 to 200 microns; the finer powders, thecoarser powders, and the much coarser powders being differentsubstances. Preferably, the finer powders have an average particle sizeof <5 to 15 microns, the coarser powders have an average particles sizeof 30 to 50 microns, and the much coarser powders have an averageparticles size of 70 to 90 microns. The proportion of finer excipientpowders may be 0.1% to 99% of the total amount of excipient powders.

In embodiments where the pharmaceutically acceptable excipient of thedry powder formulations is a mixture of finer powders and coarserpowders; the powdered granisetron may be blended with the finerexcipient powders first, and then the mixture of the powderedgranisetron and the finer powders are blended with the coarser excipientpowders. Alternatively, the powdered granisetron may be blended with thefiner excipient powders and the coarser excipient powders separately,and then each of the blended excipient mixtures (i.e., finer excipientpowders with powdered granisetron and coarser excipient powders withpowdered granisetron) are blended with each other.

In embodiments were the pharmaceutically acceptable excipient of the drypowder formulations is a mixture of finer powders, coarser powders, andmuch coarser; the powdered granisetron may be sequentially blended withthe finer excipient powders, the coarser excipient powders, and the muchcoarser excipient powders. Alternatively, the powdered granisetron isblended with the finer excipient powders, the coarser excipient powders,and the much coarser excipient powders separately, and then the mixtures(i.e., finer excipient powders with powdered granisetron, coarserexcipient powders with powdered granisetron, and much coarser excipientpowders with granisetron) are blended with each other.

The content of the powdered granisetron in the dry powder formulationsranges from 0.05% to about 100% of the total composition of formulation,preferably from about 0.05% to about 50%, from about 0.05% to about 45%,from about 0.05% to about 40%, from about 0.05% to about 35%, from about0.05% to about 30%, from about 0.05% to about 25%, from about 0.05% toabout 20%, from about 0.05% to about 15%, or from about 0.05% to about10% of the total composition of formulation.

The content of the powdered granisetron in the dry powder formulationsmay also range from about 0.1% to about 100%, from about 0.1% to about50%, from about 0.1% to about 45%, from about 0.1% to about 40%, fromabout 0.1% to about 35%, from about 0.1% to about 30%, from about 0.1%to about 25% of the total composition of formulation, from about 0.1% toabout 20%, from about 0.1% to about 15%, or from about 0.1% to about 10%of the total composition of formulation, preferably from about 1% toabout 10% of the total composition of formulation, and more preferablyfrom about 5% to about 10% of the total composition of formulation. In aparticular embodiment, with respect to the formulations, the powderedgranisetron is about 10% of the total composition of formulation.

Generally, the dry powder formulations contain 0.1-10 mg of the powderedgranisetron, preferably from 0.5-5 mg, from 1-3 mg.

In a particular embodiment, the dry powder formulations comprisegranisetron and lactose. The dry powder formulations containing lactosecomprise granisetron, finer lactose, and coarser lactose, orgranisetron, finer lactose, and much coarser lactose granisetron, orfiner lactose, coarser lactose, and much coarser lactose. For example,the dry powder formulations may comprise about 0.5 to about 5 mg ofgranisetron, about 0.001 to about 2 g of finer lactose, and about 0.001to about 2 g of coarser lactose. For example, in dry powder formulationscontaining granisetron and lactose or glucose, the amount of thegranisetron is from 0.5-5 mg, and the amount of lactose or glucose isabout 0.001 g to about 2.5 g. Preferably, the amount of granisetron isabout 0.5 to about 5 mg and the amount of lactose or glucose is about 1to about 200 mg.

In yet another particular embodiment, the dry powder formulationscomprise granisetron and glucose. The dry powder formulations containingglucose comprise granisetron, finer glucose, and coarser glucose, orgranisetron, finer glucose, coarser glucose, and much coarser glucose.In yet another particular embodiment, the dry powder formulationscomprise about 0.5 to about 5 mg of granisetron, about 0.001 to about 2g of finer glucose, and about 0.001 to about 2 g of coarser glucose. Forexample, the dry powder formulations may comprise about 0.5 to about 5mg of granisetron, about 1 to about 200 mg of finer glucose, and about 1to about 200 mg of coarser glucose.

In yet another particular embodiment, the dry powder formulationscomprise granisetron, lactose, and glucose. The dry powder formulationscomprising granisetron, lactose, and glucose may comprise granisetron,finer lactose, and coarser glucose or granisetron, finer glucose, andcoarser lactose. For example, the dry powder formulations may compriseabout 0.5 to about 5 mg of granisetron, from about 0.001 to about 2 g oflactose, and from about 0.001 to about 2 g of glucose. In one particularembodiment, the dry powder formulations comprise from about 0.5 to about5 mg granisetron, from about 0.001 to 2 g of finer lactose, and fromabout 0.001 to about 2 g of coarser glucose. In an alternativeembodiment, the formulation comprises from about 0.5 to about 5 mg ofgranisetron, from about 0.001 to about 2 g of finer glucose, and fromabout 0.001 to about 2 g of coarser lactose.

The aerosol formulations of the present invention are uniform andhomogeneous. The uniformity/homogeneity of the aerosol formulations ismeasured by drawing 3 or more samples from the formulation, dissolvingin mobile, and testing for concentration of the active pharmaceuticalingredient (API, granisetron) in the formulation by HPLC. The uniformityof the aerosol formulations is expressed by the relative standarddeviation (% RSD) of the API concentration. The aerosol formulationshave an RSD % less than 5%, less than 4%, less than 3%, less than 2.5%,less than 2.25%, less than 2.0%, less than 1.75%, less than 1.5%, lessthan 1.25%, less than 1.0%, less than 0.75%, less than 0.5%, less than0.25%, and even less than 0.25%.

The discharge capacity or percent recovery of the aerosol formulationsis measurable with a Next Generation Pharmaceutical Impactor (NGI). Inthis device, powders are drawn by vacuum into different chambersrepresenting the lung, each chamber corresponding to a different rangeof aerodynamic particle size. NGI data includes mass median aerodynamicdiameter (MMAD), and fine particle fraction (FPF). The FPF is generallyassumed to represent the fraction of particles that would deposit invivo in the “deep lungs,” or particles that have an aerodynamic diameterof equal to or less than 5 μm. The discharge capacity or percentrecovery of the aerosol formulations of the present invention is atleast 70%, at least 75%, at least 80%, at least 85%, at least 90%, atleast 91%, at least 92%, at least 93%, at least 94%, at least 95%, atleast 96%, at least 97%, at least 98%, and even at least 99%, asmeasured by NGI.

The present inventors have observed that the inclusion of fine excipientparticles increases the FPF while decreasing the MMAD. The inclusion ofcoarse excipient powders alone resulted in a FPF percent delivery of 7to 8% where the coarse particles were lactose particles having a D10 of3˜6 μm, a D50 of 20˜25 μm, and a D90 of 50˜60 μm (LACTOHALE® 201(LH201)), or lactose particles having a D10 of ˜4 μm, a D50 of ˜55 μm,and D90 a of ˜170 μm (RESPITOSE® ML001 (ML001)). However, a combinationof the coarse lactose particles ML001 (D11 of ˜4 μm, a D50 of ˜55 μm,and D90 a of ˜170 μm) with fine lactose excipient particles having aD50<5 μm and a D90≦10 μm increased the FPF percent delivery. The FPFpercent delivery increased further where the coarse particles that weremixed with the fine particle had a D10 of ˜30 μm, a D50 of ˜60 μm, and aD90 was ˜100 μm (RESPITOSE® SV003 (SV003)).

In the present invention, each of the aerosol formulations containingcoarse and fine lactose particles achieved a 3-5% increase in thedelivery of FPF when the humidity of the environment during theaerodynamic performance testing was controlled to have a relativehumidity (RH) of 50% rather than the ambient 20% RH. It is believed thatthe higher-than-ambient humidity, which is more representative of theenvironment in the human inhalation route, further increases thedisaggregation by reducing the surface-energy-induced-aggregation whenthe formulation is inhaled into the impator.

Typically, the dry powdered formulations are administered by a drypowder inhaler, a dry powder dispenser, or a dry powder delivery device.The inhaler may be a single dose or multi-dose inhaler. Suitableinhalers may include SPINHALER®, ROTAHALER®, AEROLIZER®, INHALATOR®,HANDIHALER®, DISKHALER®, DISKUS®, ACCUHALER®, AEROHALER®, ECLIPSE®,TURBOHALER®, TURBUHALER®, EASYHALER®, NOVOLIZER®, CLICKHALER®,PULVINAL®, NOVOLIZER®, SKYEHALER®, XCELOVAIR®, PULVINA®, TAIFUN®,MAGHALER®, TWISTHALER®, JETHALER®, FLOWCAPS®, XCAPS®, TWINCAPS®,CYCLOHALER®, TURBOSPIN®, AIR DPI®, ORBITAL®, DIRECTHALER®, or an inhalerthat is newly developed.

Pressurized Metered Dose Formulations (pMDI Formulations)

In another particular embodiment, the formulation is a pMDI formulationcontaining an excipient, where the excipient selected from the groupconsisting of oleates, stearates, myristates, alkylethers, alkylarylethers, sorbates, and mixtures thereof. In the pMDI formulations,the excipient may include sorbitan trioleate, isopropyl myristate, orlecithin. Additional excipients for the pMDI formulations include oleicacid or oleic acid esters and polyvinylpyrrolidone (PVP).

In certain embodiments, the pMDI formulations do not include apropellant. However, the pMDI formulations generally include apropellant, especially a hydrofluoroalkane propellant. Thehydrofluoroalkane propellants for the pMDI formulations are selectedfrom the group consisting of 1,1,1,2-tetrafluoroethane (P134a),1,1,1,2,3,3,3-heptafluoro-n propane (P227), and mixtures P134a and P227.Another suitable propellant for the pMDI formulations is 2H,3H-perfluoropentane (HPFP).

The pMDI formulations may further include a diluent or a mixture ofdiluents. The pMDI formulations may also include a surfactant or amixture of surfactants. Exemplary surfactants are selected from thegroup consisting of alkylethers, alkyl arylethers, laurates, myristates,oleates, sorbates, stearates, propylene glycol, lipids, and combinationsthereof. Preferred surfactants are oleates, sorbates, stearates,propylene glycol, and combinations thereof.

In certain embodiments, the pMDI formulations do not comprise aco-solvent. However, in alternate embodiments, the pMDI formulationscontain a co-solvent or a mixture of co-solvents. The pMDI formulationsmay include a co-solvent selected from C₂₋₆ alcohols, polyols, cineole,citral, lactic acid oligomers, or poly(ethylene glycols).

The pMDI formulations may comprises ethanol as a co-solvent. The contentof ethanol in the pMDI formulations is no more than 25% (w/w), no morethan 20% (w/w), no more than 15% (w/w), no more than 10% (w/w), no morethan 8% (w/w), preferably no more than 5% (w/w) of ethanol, no more than2.5% (w/w), and more preferably no more than 1% (w/w) of ethanol.

The content of the granisetron in the pMDI formulations is from about0.01% to about 20%, from about 0.01% to about 10%, from 0.01% to about5%, from about 0.01% to about 2%, from about 0.01% to about 1%, or fromabout 0.01% to about 0.5% of the total composition of the formulation.In a particular embodiment, with respect to the pMDI formulations, thecontent of the granisetron is from about 0.1% to about 0.2% of the totalcomposition of the formulation.

In a particular embodiment, the pMDI formulations comprise granisetronand at least one selected from P134a and P227. In such pMDIformulations, based on the size of the canister, the amount ofgranisetron is from 0.1-100 mg, and the amount of P134a and/or P227 isabout 0.5 g to about 50 g. In certain embodiments, the pMDI formulationcontains granisetron and P134a, where the amount of granisetron is fromabout 0.1 to about 100 mg, preferably about 1-50 mg, and the amount ofP134a is from 0.5 g to about 50 g, preferably about 10 g to 20 g.Similarly, the pMDI formulation may contains granisetron and P227, wherethe amount of granisetron is from about 0.1 to about 100 mg, preferablyabout 1-50 mg, and the amount of P227 is from 0.5 g to about 50 g,preferably about 10 g to 20 g. In pMDI formulations containinggranisetron, P134a, and P227, the amount of granisetron is from about0.1 to about 100 mg, preferably about 1-50 mg, the amount of P134a about0.5 g to about 50 g, and the amount of P227 is about 0.5 g to about 50g.

In further embodiments, the pMDI formulation comprises granisetron,P134a and/or P227, and isopropyl myristate. In certain embodiments, thepMDI formulations contain granisetron, P134a and/or P227, and propyleneglycol. In addition, the pMDI formulations may contain granisetron,P134a and/or P227, and isopropyl laurate.

In certain embodiments, the pMDI formulations of the present inventioncontains granisetron that is a solute in a solution, and the solvent isselected from a group consisting of propellants, hybrid propellants,cosolvents, cosolvent mixture, organic solvents, water, buffers, andcombinations thereof.

In certain embodiments, the pMDI formulations of the present inventioncontains granisetron that is in a powdered form in a suspension, and thesuspension is in a liquid selected from a group consisting ofpropellants, hybrid propellants, propellants with stabilizers,propellants with surfactants, propellants with diluents, propellantswith cosolvents, water, buffer, and combinations thereof.

In a particular embodiment, the pMDI formulations of the presentinvention contains granisetron that is a solute in a solution, whereinthe solubility of granisetron is more than 0.01% w/w, more than 0.1%w/w, or more than 1%.

In a particular embodiment, the pMDI formulations of the presentinvention contains granisetron that is in a powdered form in asuspension, wherein the solubility of granisetron is less than 0.1% w/w,less than 0.01% w/w, less than 0.001%, or less than 0.0002% w/w.

Typically, the pMDI formulations are administered by an actuator, ametered dose inhaler, an aerosol dispenser, or an aerosol deliverydevice.

The present invention also provides methods of treating a condition ofnausea or vomiting, wherein the method comprises pulmonaryadministration of a pharmaceutically acceptable amount of the aerosolformulations of the present invention; and wherein the formulations areadministered into the pulmonary tract by inhalation. The pulmonarydelivery of granisetron to a subject is carried out by having thesubject inhale a pharmaceutically acceptable amount of the aerosolformulation of the present invention through the subject's mouth.Additionally or alternatively, the pulmonary delivery of granisetron toa subject is accomplished by having the subject inhale apharmaceutically acceptable amount of the aerosol formulation of thepresent invention through the subject's nose.

In one embodiment, the pharmaceutically acceptable amount is produced byintroducing the granisetron into a gas stream. Specifically, thepharmaceutically acceptable amount is produced by introducing thegranisetron into a gas stream, and the gas stream is the subject'sinspiratory breath.

In one embodiment, with respect to the methods, the pharmaceuticallyacceptable amount contains about 0.1 mg to about 25 mg of granisetronand the total dosage is from about 0.1 mg to about 25 mg.

Preferably, the pharmaceutically acceptable amount contains less thanabout 25 mg, less than about 20 mg, less than about 15 mg, less thanabout 10 mg, less than about 5 mg, or less than about 3 mg ofgranisetron. In another embodiment, the pharmaceutically acceptableamount contains more than about 0.1 mg, more than about 0.5 mg, morethan about 1 mg, more than about 2 mg, or more than about 3 mg ofgranisetron. More preferably, the pharmaceutically acceptable amountcontains about 3 mg of granisetron.

The total dosage of granisetron per day is about 0.1 mg to about 25 mg,about 0.2 mg to about 10 mg, about 0.5 mg to about 8 mg, about 1 mg toabout 5 mg, about 2 mg to about 3 mg of granisetron per day.

With the dry powder formulations, the pharmaceutically acceptable amountof granisetron is produced by releasing blended powders containingpowdered granisetron from a container such as a capsule or a blister byusing a device such as a dry powder inhaler. A device may be loaded withone or more capsules/blisters at a time. The pharmaceutically acceptableamount is produced through one, two or multiple actuations. Thereleasing amount of one actuation is preferably equal to the formulationstored in one capsule or blister. Whereas with the pMDI formulations,the pharmaceutically acceptable amount of granisetron is produced byreleasing a propellant containing granisetron from a container such as acanister by using a device such as a pMDI inhaler. The canister may beactuated by pressing an actuator or by inhalation. The pharmaceuticallyacceptable amount is produced through one, two or multiple actuations.The releasing amount of one actuation is preferably less than theformulation stored in one canister. The releasing amount is metered.

After administration to a subject, granisetron in blood plasma reaches amaximum concentration (Cmax) of 1-5000 ng/mL in the subject, preferablyof 2-2000 ng/mL, and more preferably of 5-1000 ng/mL in a subject.

Delivery of the aerosol formulations through the pulmonary tract of asubject provides a Cmax of granisetron in blood plasma that is about0.05 to about 1, about 0.1 to about 0.8, about 0.2 to about 0.6, orabout 0.3 to about 0.4 times of the Cmax achieved following intravenousbolus delivery of granisetron. Moreover, delivery of the aerosolformulations through the pulmonary tract of a subject to provides a Cmaxof granisetron in blood plasma that is about 0.1 to about 1.5, about 0.2to about 1.25, about 0.4 to about 1.1, or about 0.8 to about 1.05 timesof the Cmax achieved following oral delivery of granisetron.

In addition, the granisetron in blood plasma reaches maximumconcentration at (Tmax) 1 minute to 2 hours after dose in a subject,preferably the Tmax is 2 minutes to 1 hour after dose in a subject, andeven 5 minutes to 30 minutes after dose in a subject. Delivery of theaerosol formulations through the pulmonary tract of a subject provides aTmax of granisetron in blood plasma that is about 0.01 to about 1.5,about 0.05 to about 1, about 0.1 to about 0.8, about 0.2 to about 0.6,or about 0.3 to about 0.4 times of the Tmax achieved following oraldelivery of granisetron.

The area under curve (AUC) of granisetron in blood plasma of a subjectranges from 2-50000 ng*h/mL, preferably from 5-20000 ng*h/mL, and morepreferably from 10-10000 ng*h/mL. Delivery of the aerosol formulationsthrough the pulmonary tract produces a mean AUC of granisetron in bloodplasma that is about 0.1 to 1.5, about 0.2 to about 1.25, about 0.4 toabout 1.1, or about 0.8 to about 1.05 times of the mean AUC achievedfollowing intravenous bolus delivery of granisetron. In one embodiment,the AUC is about the same as that is achieved following intravenousbolus delivery of granisetron. Similarly, delivery of the aerosolformulations through the pulmonary tract produces a mean total AUC ofgranisetron in blood plasma that is about 0.1 to about 1.5, about 0.2 toabout 1.25, about 0.4 to about 1.1, or about 0.8 to about 1.05 times ofthe AUC achieved following oral delivery of granisetron. In oneembodiment, the AUC is about the same as that is achieved following oraldelivery of granisetron.

In one embodiment, the aerosol and dry powder formulations and themethod are useful for the reduction, elimination, or prevention ofnausea and vomiting, where the nausea and vomiting arechemotherapy-induced nausea and vomiting, radiation-induced nausea, orvomiting and post-operative nausea and vomiting.

In one embodiment, the subject is a cancer patient; in particular, acancer patient undergoing chemotherapy, radiotherapy, or a surgery.Additionally, the cancer patient may suffer from nausea and/or vomitingrelated to the chemotherapy, radiotherapy, or surgery.

The powdered granisetron of the aerosol formulations may be prepared bydissolving the bulk granisetron in distilled water with co-solvents, toform a solution; spray drying the solution, to obtain poweredgranisetron; separating and filtering the powdered granisetron accordingto their sizes with a cyclone; milling and grinding the powderedgranisetron to further reduce the size of powered granisetron; andcollecting and analyzing the precipitated granisetron powder. During themilling and grinding, the milling and grinding forces and timing areoptimized so that the particle size distribution of the processedgranisetron is from about 0.5 to about 5 μm; and the mean volumediameter is of about 2-3 μm.

The powdered granisetron of the aerosol and dry powder formulations mayalso be prepared by dissolving the bulk granisetron in distilled water,to form a solution; spray drying the solution with temperature in adrying vessel; separating and filtering the powdered granisetronaccording to their sizes with a cyclone; and collecting and analyzingthe precipitated granisetron powder. The flow rate of the solution, thetemperature and the flow rate of the drying air, and other parametersare optimized so that the granisetron precipitation is crystalline; andthe particle size distribution is of about 0.5 to about 5 μm; and themean volume diameter is of about 2-3 μm.

Alternatively, the powdered granisetron of the aerosol and dry powderformulations may be prepared by dissolving the bulk granisetron insupercritical fluid CO₂, to form a solution; depressuring the solutionin a depressurization vessel; and collecting and analyzing theprecipitated granisetron powder. The temperature and the pressure of theSCF CO₂ (before the precipitation) and the depressurization vessel, andother parameters are optimized so that the granisetron precipitation iscrystalline; and the particle size distribution is of about 0.5 to about5 μm; and the mean volume diameter is of about 2-3 μm.

For dry powder formulations, the powdered granisetron may be mixed withone or more excipients, to form the dry powder formulation. The obtaineddry powder formulation is then loaded into a dry powder inhaler.Alternatively, for pMDI formulations, the granisetron may be mixed witha pressurized propellant or mixture of propellants, to form the pMDIformulation. The obtained pMDI formulation is then filled intocanisters, which are installed into a metered-dose inhaler.

Thus, the present invention also provides pharmaceutical aerosolinhalation formulations or inhalable pharmaceutical aerosol formulationsfor pulmonary administration to a subject, wherein

-   -   the formulation is a dry power formulation and comprises        powdered granisetron;    -   the powdered granisetron is produced by a particle engineering        process;    -   the MMAD of powdered granisetron is between 1 and 3 microns;    -   the formulation may comprise excipient(s);    -   the formulation is administered into the pulmonary tract by        inhalation; and the subject is a cancer patient suffering from        nausea that is related to chemotherapy, radiotherapy, or        surgery;    -   or the formulation is a pMDI formulation comprises granisetron;    -   the granisetron may be powered granisetron produced by a        particle engineering process;    -   the MMAD of powdered granisetron is between 1 and 3 microns;    -   the formulation may comprise excipient(s) and at least a        hydrofluoroalkane;    -   the formulation is administered into the pulmonary tract by        inhalation; and the subject is a cancer patient suffering from        nausea that is related to chemotherapy, radiotherapy, or        surgery.

The powdered granisetron may be produced by a spray drying process thatcomprises:

-   -   i) dissolving the bulk granisetron in distilled water, to form a        solution;    -   ii) spray drying the solution in a spray dryer;    -   iii) separating and filtering the granisetron particles        according to their sizes with a cyclone; and    -   iv) collecting and analyzing the precipitated granisetron        powder.

In another embodiment, the powdered granisetron is produced by asupercritical fluid process that comprises:

-   -   i) dissolving the bulk granisetron in supercritical fluid CO₂,        to form a solution;    -   ii) depressuring the saturated solution in a depressurization        vessel; and    -   iii) collecting and analyzing the precipitated granisetron        powder.

In one embodiment, the formulation is a pharmaceutical dry powderinhalation formulation that contains lactose and/or glucose as anexcipient, where the amount of granisetron is about 0.05 to 100 wt %,about 1 to 50 wt %, about 2 to 20 wt %, or about 5 to 15 wt % of theexcipient. In another embodiment, the formulation is a pharmaceuticalpMDI inhalation formulation that contains P134a and/or P227 aspropellants, where the amount of granisetron is about 0.01 to 20 wt %,about 0.01 to 1 wt %, or about 0.01 to 0.5 wt % of the propellant.

Delivery of the pharmaceutical aerosol inhalation formulations into thepulmonary tract of a subject provides a Cmax of granisetron in bloodplasma that is about 20-80% of the Cmax achieved following intravenousbolus delivery of granisetron. The Cmax from delivery into the pulmonarytract may be about the same as the Cmax achieved following oral deliveryof granisetron.

Delivery of the pharmaceutical aerosol inhalation formulations into thepulmonary tract of a subject provides Tmax of granisetron in bloodplasma that is less than the Tmax achieved following oral delivery ofgranisetron.

Delivery of the pharmaceutical aerosol inhalation formulations into thepulmonary tract of a subject provides also provides an AUC ofgranisetron in blood plasma that is about the same as the AUC achievedfollowing intravenous bolus or oral delivery of granisetron.

Additional embodiments within the scope provided herein are set forth innon-limiting fashion elsewhere herein and in the examples. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting in any manner.

Pulmonary Aerosol Formulations of the Present Invention

As described herein, the aerosol formulations of the present inventioncomprise granisetron and the formulations are useful for pulmonarydelivery via inhalation. The active drug granisetron when administeredby inhalation must penetrate deep into the lungs in order to showphysiological action. In order to achieve this, the granisetron inhaledshould be in the powdered form. Preferably, the MMAD of granisetron drugdoes not exceed about 5 μm.

Powdered Granisetron

The powdered granisetron can be prepared by processes of micronization,such as mechanical grinding, attrition by jet milling, solutionprecipitation, spray drying, lyophilization, and supercritical fluidprocesses.

Spray dying followed by a cyclone separation/filtering process mayproduce respirable particles rapidly and efficiently.

Direct controlled crystallization using an antisolvent precipitationtechnique may produce respirable particles with expected shapes. Theparticle size may be controlled by using one or more growth-retardingstabilizing additives.

Supercritical fluid processes may be used to produce respirableparticles of the desired size. The supercritical processes may be usedto prepare powdered granisetron may include rapid expansion, solutionenhanced diffusion, gas-anti solvent, supercritical antisolvent,precipitation from gas-saturated solution, precipitation with compressedantisolvent, aerosol solvent extraction system, or combinations of theforegoing. Particularly, the typical process can be rapid expansion ofsupercritical solution (RESS).

The powdered granisetron prepared by the above processes may have anMMAD between 0.5 and 5 μm.

The amount of the powdered granisetron in the formulation may be about0.01% to about 100% of the total composition of formulation.Particularly, the amount of the powdered granisetron may be 0.05% toabout 20% of the total composition of formulation.

Dry Powder Formulations

Excipients

The aerosol formulations of the present invention may comprisepharmaceutically acceptable excipients. The typical excipients which maybe used in the formulation include carbohydrates, amino acids,polypeptides, lipids, salts, polyalcohols, galactose, mannose, sorbose,lactose, glucose, trehalose, raffinose, maltodextrins, dextrans,mannitol, xylitol, alanine, glycine, tryptophan, tyrosine, leucine,phenylalanine, and mixtures or combinations thereof.

pMDI Formulations

Propellants

The pMDI formulations of the present invention may comprisepharmaceutically acceptable propellants. Typical propellants includehydrofluoroalkane (HFA) propellants. The hydrofluoroalkane propellantswhich may be used in the pMDI formulations include1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3-heptafluoro-n propane(P227), and mixtures of P134a and P227.

Surfactants

The pMDI formulations of the present invention may comprisepharmaceutically acceptable surfactants. Typical surfactants includealkylethers, alkyl arylethers, laurates, myristates, oleates, sorbates,stearates, propylene glycol, lipids, and combinations thereof.

Co-Solvents

The pMDI formulations of the present invention may comprisepharmaceutically acceptable co-solvents. Typical co-solvents includeC₂₋₆ alcohols, polyols, and combinations thereof. Particularly, theco-solvent may be ethanol.

Exemplary Formulations of the Invention

The following examples illustrate certain embodiments of the disclosureand are not intended to be construed in a limiting manner.

Exemplary Formulations of the Invention

Formulation 1

Ingredient Amount Granisetron Fine Powder 5 mg

Formulation 2

Ingredient Amount Granisetron Fine Powder  5 mg Lactose Powder 45 mg

Formulation 3

Ingredient Amount Granisetron Fine Powder  5 mg Glucose Powder 45 mg

Formulation 4

Ingredient Amount Granisetron Fine Powder  2 mg Lactose Powder 18 mg

Formulation 5

Ingredient Amount Granisetron Fine Powder 5 mg Finer Lactose Powder 4.5mg Coarser Lactose Powder 40.5 mg

Formulation 6

Ingredient Amount Granisetron Fine Powder  2 mg Glucose Powder 18 mg

Formulation 7

Ingredient Amount Granisetron Fine Powder 5 mg Finer Glucose Powder 4.5mg Coarser Glucose Powder 40.5 mg

Formulation 8

Ingredient Amount Granisetron Fine Powder 2 mg Lactose Powder 9 mgGlucose Powder 9 mg

Formulation 9

Ingredient Amount Granisetron 20 mg HFA 134a Propellant 10 g

Formulation 10

Ingredient Amount Granisetron 20 mg HFA 134a Propellant 10 g IsopropylMyristate 0.1 g

Formulation 11

Ingredient Amount Granisetron 20 mg HFA 227 Propellant 10 g

Formulation 12

Ingredient Amount Granisetron 20 mg HFA 227 Propellant 10 g IsopropylMyristate 0.1 g

Formulation 13

Ingredient Amount Granisetron 20 mg HFA 134a Propellant 20 g

Formulation 14

Ingredient Amount Granisetron 20 mg HFA 227 Propellant 20 g

Formulation 15

Ingredient Amount Granisetron 20 mg HFA 134a Propellant 10 g HFA 227Propellant 10 g

Formulation 16

Ingredient Amount Granisetron 20 mg HFA 134a Propellant 10 g HFA 227Propellant 10 g Isopropyl Laurate 0.1 g

Formulation 17

Ingredient Amount Granisetron 2 mg HFA 134a Propellant 1 g

Formulation 18

Ingredient Amount Granisetron 2 mg HFA 134a Propellant 1 g IsopropylMyristate 0.01 g

Formulation 19

Ingredient Amount Granisetron 2 mg HFA 227 Propellant 1 g

Formulation 20

Ingredient Amount Granisetron 2 mg HFA 227 Propellant 1 g IsopropylMyristate 0.01 g

Formulation 21

Ingredient Amount Granisetron 2 mg HFA 134a Propellant 2 g

Formulation 22

Ingredient Amount Granisetron 2 mg HFA 227 Propellant 2 g

Formulation 23

Ingredient Amount Granisetron 2 mg HFA 134a Propellant 1 g HFA 227Propellant 1 g

Formulation 24

Ingredient Amount Granisetron 2 mg HFA 134a Propellant 1 g HFA 227Propellant 1 g Isopropyl Laurate 0.01 g

Example 1: Preparation of Spray Dried Granisetron Fine Powder

Powdered granisetron was prepared by spray drying with SPRAY DRYERSD-MICRO™ (manufactured by GEA Process Engineering, Inc., Columbia, Md.,USA). The experiments were done at GEA Process Engineering, Inc.,Columbia, Md., USA.

TABLE 1 Parameters of Spray Drying to Prepare Granisetron Fine PowderInlet Outlet Spray Nozzle Conc. N₂ Temp. Temp. Rate Diameter Run (wt %)(kg/hr) (° C.) (° C.) (g/min) (mm) 1 2.94 30 170 85 10.6 0.5 2 2.94 30170 85 10.9 0.5 3 2.94 30 195 100 9.9 0.5

Example 2: Particle Size Distribution of Spray Dried Granisetron FinePowder

The Particle Size Distribution of the Granisetron Fine Powder, preparedby Spray Drying using the above parameters was measured by MalvernMastersizer (Malvern Instruments, UK) at GEA Process Engineering, Inc.,Columbia, Md., USA.

The typical Particle Size Distribution:

D10: 1.01 μm

D50: 2.33 μm

D90: 5.34 μm

Cumulative % on <9 μm: 98.0%

FIG. 2 shows the typical Particle Size Distribution of the Spray DriedGranisetron.

Example 3: Preparation of Jet Milled Granisetron Fine Powder

Granisetron HCl was milled with a Model-00 JET-O-MIZER (manufactured byFluid Energy Processing and Equipment Company). Pushing nozzle andgrinding nozzle pressure were both set to 110 psi. The granisetron HClparticles were milled for 5 cycles and the particles were measured afterthe first, third, and fifth cycles. After 5 cycles, it was determinedthat the particle size would not continue to decrease with additionalmilling. The jet milling experiments were conducted at Drug DynamicsInstitute, College of Pharmacy, The University of Texas at Austin,Austin, Tex., USA.

Example 4: Particle Size Distribution of Jet Milled Granisetron FinePowder

The particle size distributions of the jet milled granisetron finepowder were measured after the first cycle, the third cycle, and thefifth cycle of jet milling with the above parameters. The particle sizedistributions were measured by Malvern Spraytec (Malvern Instruments,UK) operated at 90 LPM during over a 4 second duration. The experimentswere done at Drug Dynamics Institute, College of Pharmacy, TheUniversity of Texas at Austin, Austin, Tex., USA.

The typical particle size distribution of the milled granisetron isshown in Table 2.

TABLE 2 Particle size distribution of jet milled granisetron as afunction of milling cycle. Milling Cycle D10 D50 D90 0 3.77 μm 50.21 μm 445.02 μm  1 2.22 μm 7.01 μm 20.59 μm  3 1.44 μm 3.99 μm 9.90 μm 5 1.59μm 3.79 μm 8.13 μm

FIG. 3 shows the typical particle size distribution of the jet milledgranisetron as a function of milling cycle. As shown in FIG. 3, the d50after the fifth milling cycle was 3.79 μm, which is within therespirable range. Furthermore, approximately 75% of the mass was lessthan 5 μm in diameter.

Example 5: Fine Particle Fraction by Next Generation Impaction

The fine particle fraction (FPF) of the dry powder granisetron aerosolformulations was measured by Next Generation Impaction (NGI) at DrugDynamics Institute, College of Pharmacy, The University of Texas atAustin, Austin, Tex., USA.

The in vitro aerodynamic performance of the dry powder granisetronaerosol formulations were tested by NGI. The results reflect the in vivo(pulmonary) aerodynamic performance of the following aerosolformulations. The Next Generation Impactor used in this embodiment wasmade by Copley Scientific, GB.

The Exemplary Formulation 1 (EF1) measured by NGI included:

Milled Granisetron (MG): 5 mg;

Coarse Lactose (LH201): 45 mg;

Fine Lactose: N/A.

The Exemplary Formulation 2 (EF2) that was measured by NGI was:

Milled Granisetron (MG): 5 mg;

Coarse Lactose (ML001): 45 mg;

Fine Lactose: N/A.

The Exemplary Formulation 3 (EF3) that was measured by NGI was:

Milled Granisetron (MG): 5 mg;

Coarse Lactose (ML001): 40.5 mg;

Fine Lactose (LH300): 4.5 mg.

The Exemplary Formulation 4 (EF4) that was measured by NGI was:

Milled Granisetron (MG): 5 mg;

Coarse Lactose (SV300): 40.4 mg;

Fine Lactose (LH300): 4.5 mg.

The lactose in the EF1 was LACTOHALE® 201 (LH201; D10 was 3˜6 μm, D50was 20˜25 μm, D90 was 50˜60 μm) made by DFE Pharma, Germany. The lactosein EF2 was RESPITOSE® ML001 (ML001, milled; D10 was ˜4 μm, D50 was ˜55μm, D90 was ˜170 μm) made by DFE Pharma, Germany. The lactose in EF3 wasa mixture of RESPITOSE® ML001 and LACTOHALE® 300 (LH300, micronized; D50was <5 μm, D90 was ≦10 μm) made by DFE Pharma, Germany. The Lactose inEF4 was a mixture of RESPITOSE® SV003 (SV003, sieved; D10 was ˜30 μm,D50 was ˜60 μm, D90 was ˜100 μm) made by DFE Pharma, Germany andLACTOHALE® 300.

Each of the EF blends were produced with a TURBULA® Shaker Mixer. Forthe blends that included fines (e.g., ML001/LH300), the coarse lactoseand the fine lactose were blended together before the addition of thegranisetron. All blending was performed at 48 rpm for 2 cycles of 15minutes. After a blending cycle was complete, the contents were passedthrough a 300 μm aperture sieve. All blends produced were tested forBatch Uniformity/Potency. Batch Uniformity/Potency was tested by drawing3 samples from each blend. Each sample was measured by HPLC intriplicate. A % RSD below 2.5% was considered adequate uniformity forthis study. Potency was calculated as an average of all 9 measurements.% RSD was also based on all 9 measurement.

TABLE 3 Blend Uniformity and Potency Testing LH201 ML001 ML001/LH300SV003/LH300 Potency (%) 10.55 10.25 9.63 10.03 % RSD 0.12 1.62 2.15 0.58

HandiHaler® was used as the model Dry Powder Inhaler Device. The flowrate was 60 LPM (>4 kPa), the duration was 4 seconds, the total volumewas 4 L. Testing was performed under ambient and controlled environmentconditions. All four exemplary aerosol formulations (EF1, EF2, EF3, andEF4) were tested at ambient conditions. The ambient conditions wereapproximately 22° C. and 20% relative humidity (RH). Both formulationscontaining fine lactose (EF3 and EF4) were also tested at the controlledenvironment conditions. The controlled environment conditions were 23°C. and 50% RH.

The number of NGI runs at ambient conditions were: EF1, n=3; EF2, n=3;EF3, n=3; and EF4, n=3.

All NGI runs under ambient conditions exhibited a percent recoverygreater than 90%. Aerosol particle size distribution (APSD) ofindividual NGI runs are given in FIGS. 4-7. Mean aerosol performancedata are given in Table 4.

TABLE 4 The Mean APSD Parameters of EF1-EF4 Measured by NGI at ~22° C.and 20% RH. RSD RSD RSD RSD (%, (%, (%, (%, Parameter (Unit) EF1 EF1)EF2 EF2) EF3 EF3) EF4 EF4) Amount of Drug 5340 1 5272 3 5116 2 5300 1Loaded (μg) % Recovered 98 1 100 1 91 2 92 8 Preseparator, % 21 5 21 117 2 14 5 of Loaded Delivered Dose, 78 5 83 1 78 3 75 7 % of Loaded FineParticle 7 8 8 4 11 4 15 8 Fraction (≦5 μm), % of Delivered Mass Median6 <1 6 2 6 1 5 2 Aerodynamic Diameter (μm)

The FPF of EF1-EF4 under ambient conditions were 7, 8, 11, and 15%,respectively. FPF was defined as percent of particles less than 5 μm.The MMAD of EF1-EF4 under ambient conditions was 6 μm, 6 μm, 6 μm, and 5μm, respectively.

Notably, the inclusion of fines increased the FPF, and reduced the MMAD.EF4, the blend of RESPITOSE® SV003 and LACTOHALE® 300, exhibited thehighest FPF and the lowest MMAD.

The numbers of NGI runs at the controlled environment conditions (23°C., 50% RH) were: EF3, n=3; and EF4, n=3.

All NGI runs under the controlled environment conditions exhibited apercent recovery greater than 90%. Aerosol particle size distribution(APSD) of individual NGI runs are given in FIGS. 8 and 9. Mean aerosolperformance data are given in Table 5.

TABLE 5 The Mean APSD Parameters of EF1-EF4 Measured by NGI at ~22° C.and 20% RH. RSD RSD Parameter (Unit) EF3 (%, EF3) EF4 (%, EF4) Amount ofDrug Loaded (μg) 5006 1 5061 3 % Recovered 93 2 93 2 Preseparator, % ofLoaded 18 10 15 13 Delivered Dose, % of Loaded 78 1 76 4 Fine ParticleFraction 16 5 18 9 (≦5 μm), % of Delivered Mass Median Aerodynamic 5.60.4 5.0 2.1 Diameter(μm)

The FPF of EF3 and EF4 under the controlled environment conditions 16and 18%, respectively. FPF was defined as percent of particles less than5 μm. The MMAD of EF3 and EF4 under the controlled environmentconditions was 5.6 μm and 5.0 μm, respectively.

A comparison between the EF3 and EF4 at ambient conditions (˜22° C., 20%RH) versus the controlled environment conditions (23° C., 50% RH) showsa further increase in the FPF, but also a decrease in the depositionlevels in the throat of the NGI.

In comparing all of the aerosol formulations at ambient and controlledconditions, EF4, the blend of RESPITOSE® SV003 and LACTOHALE® 300,exhibited the highest FPF and the lowest MMAD. Both aerosol formulationscontaining fine lactose, EF3 (ML001/LH300) and EF4 (SV003/LH300)demonstrated a further improvement in performance when tested at 50% RHrather than 20% RH. The average FPF of EF4 (SV003/LH300) at 20% RH and50% RH was 15% and 18%, respectively.

Example 6: Solubility of Granisetron in pMDI Formulations

The solubility of granisetron was measured in a pMDI medium of HFA 134as well as a mixture of HFA 134 and ethanol.

The solubility results with HFA 134 alone were as follows:

pMDI Medium ~24 Hours 10 days HFA 134a (μg/mL) 2.370 13.16 3.808 14.840.336 10.26 — 11.51 — 15.77 Average (RSD) 2.171 (0.803) 13.11 (0.174)As shown above, the solubility of the granisetron in a propellant alone,HFA 134a, was 2.171 μg/mL after 24 hours, and 13.11 μg/mL after 10 days.Since the gravity of the HFA 134a is 1.21 g/mL, the above results areequal to 0.00018% w/w and 0.00108% w/w, respectively after 24 hours and10 days.

The solubility of granisetron in a mixture of HFA 134 and a cosolvent,ethanol, was also conducted. As shown in the following Table, thesolubility results were 85.483 μg/mL after 24 hours, and 82.36 μg/mLafter 10 days. The results are equal to 0.00706% w/w, and 0.00681% w/wrespectively.

pMDI Medium ~24 Hours 10 days HFA 134a with Ethanol (9:1) 90.781 79.88(μg/mL) 84.173 74.29 81.496 86.6 — 97.99 — 73.93 Average (RSD) 85.483(0.056) 82.36 (0.125)

Example 7: pMDI Examples—In Vitro Performance

From the foregoing description, various modifications and changes in thecompositions and methods provided herein will occur to those skilled inthe art. All such modifications coming within the scope of the appendedclaims are intended to be included therein.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

REFERENCES

-   Hornby, P (2001). “Central neurocircuitry associated with emesis”.    The American Journal of Medicine 111 (8): 106S-112S. PMID 11749934-   Aapro, M. (2004). “Granisetron: an update on its clinical use in the    management of nausea and vomiting”. Oncologist 9 (6): 673-686. PMID    15561811-   Chow, A. H.; Tong, H. H.; Chattopadhyay, P.; Shekunov, B. Y. (2007).    “Particle engineering for pulmonary drug delivery”. Pharmaceutical    Research 24 (3): 411-437. PMID 17245651

1. A dry powder aerosol formulation for use in a dry powder inhaler,comprising: granisetron having a mean geometric diameter of between 1-3microns; and a pharmaceutically acceptable excipient wherein theexcipient is a mixture of coarse and fine particle lactose; and thecoarse particle lactose has a D10 of about 3-6 μm, or a D90 of about 170μm or has an average particle size of 50-200 μm; the fine particlelactose has a D50 of less than 5 μm; and the formulation has arespirable fraction (RPF) of 50% or more, when tested using a NextGeneration Impactor (NGI).
 2. The formulation of claim 1, wherein thecoarse lactose particle has average particle size of 50 to 90 μm.
 3. Theformulation of claim 1, wherein the coarse lactose particle has averageparticle size of 50 to 60 or 65 to 85 μm.
 4. The formulation of claim 1,wherein the coarse lactose particle has average particle size of 70 to80 μm.
 5. A method of treating nausea or vomiting, the methodcomprising: administering the formulation of claim 1 to a subject inneed thereof, wherein the formulation is administered into the pulmonarytract of the subject by inhalation
 6. The formulation of claim 1,wherein the coarse lactose particle has a D10 of about 4 μm.
 7. Theformulation of claim 1, wherein the coarse lactose particle has a D90 ofabout 170 μm.
 8. The formulation of claim 1, wherein the fine lactoseparticle has a D90 of less than 10 μm.
 9. The formulation of claim 1,wherein granisetron is about 15% of total composition of theformulation, or about 10% of the total composition of the formulation,or about 5% of the total composition of the formulation.
 10. Theformulation of claim 1, wherein the ratio of granisetron to lactose isabout 1:9.
 11. The formulation of claim 1, wherein the ratio of coarseto fine lactose is about 9:1
 12. The formulation of claim 1, whereingranisetron is more than about 0.1 mg and less than about 10 mg.
 13. Theformulation of claim 1, wherein granisetron is more than about 0.5 mgand less than about 5 mg.
 14. The formulation of claim 1, wherein themass median aerodynamic diameter (MMAD) of granisetron is between 0.5and 5 microns.
 15. The formulation of claim 1, wherein the mass medianaerodynamic diameter (MMAD) of granisetron is at least 2 microns; and atmost 3.5 microns.
 16. The formulation of claim 1, wherein theformulation has a fine particle fraction (FPF) of at least 55%, whentested using a Next Generation Impactor (NGI).
 17. The formulation ofclaim 1, wherein the formulation, when delivered through the pulmonarytract produces a mean area under curve (AUC) of granisetron in bloodplasma that is about 0.8 to 1.05 times of the mean AUC achievedfollowing intravenous bolus delivery of granisetron.
 18. The formulationof claim 1, wherein the formulation, when delivered through thepulmonary tract produces a mean area under curve (AUC) of granisetron inblood plasma that is about the same as the mean AUC achieved followingintravenous bolus delivery of granisetron.
 19. The formulation of claim1, wherein the formulation, when delivered through the pulmonary tractproduces a maximal concentration (Cmax) of granisetron in blood plasmathat is about 0.2 to 0.6 times of the mean Cmax achieved followingintravenous bolus delivery of granisetron.
 20. The formulation of claim1, wherein the formulation, when delivered through the pulmonary tractproduces a maximal concentration (Cmax) of granisetron in blood plasmathat is about 0.3 to 0.4 times of the mean Cmax achieved followingintravenous bolus delivery of granisetron.